Scarce information has been recorded about Native American use of the Little Pend Oreille region. A few trails, collectively called Calispel Trail, were used by interior Salish-speaking Indians and others traveling between two culturally important areas--the salmon fishery at Kettle Falls on the Columbia River, and the camas gathering grounds in the Pend Oreille Valley.

David Thompson, from the Canada-based North West Company, was the first European to record exploration of the Colville valley in the early 1800s. The Hudson Bay Company established a main trading depot in the Colville area in 1825. Missionaries, miners, and merchants followed, and Colville became an important economic center.

The land reveals historic evidence of homesteading, logging, railroading, and mining dating from the 1890s. Lilac bushes mark the spot where the Bear Creek School stood, one of two schools once located on refuge land. A short walk from the old school site lies the Biarly Post Office and home of the Christianson family. The Christiansons cleared enough land to raise a cash crop of potatoes or hay.

Between 1891 and 1925, more than 180 individual homestead claims were patented on the refuge. About one-third of these claims were sold to timber companies, with the rest going to homesteaders who worked hard to make a living in this harsh climate. Cleared fields, orchard trees, cabin remnants, and place names are the legacies of the homesteading era.

Winslow Logging Company began building logging railroad into the Little Pend Oreille River Valley in 1909. The railroad eventually totaled 20 miles. About 16 miles of the old grade, as well as scattered ties and decaying trestles, can be traced through the western flank of the refuge. Several refuge campgrounds were originally logging camps for Winslow's crews, including Camp 1 (River Camp), Camp 2 (Cottonwood Camp), and Horse Camp. Horses were used extensively to log huge ponderosa pine, fir, and cedar trees.

When the Great Depression hit in the 1930s, many people gave up and left the area. Others sold or traded their land for more productive land. Under President Franklin D. Roosevelt's New Deal, the Federal government began programs to reduce the impact of the depression. One program involved the acquisition and retirement of marginal farmland through an agency called the Resettlement Administration. Approximately 27,000 acres of refuge lands originated from this resettlement effort.

Little Pend Oreille Refuge was established in May 1939 by Executive Order of President Roosevelt as a breeding ground for migratory birds and other wildlife.